Genetic basis of nicotine withdrawal in a reduced complexity cross

降低复杂性杂交中尼古丁戒断的遗传基础

• 批准号: 9920699
• 负责人: M. Imad Damaj
• 金额: $ 58.57万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920699
• 关键词: Affective; Aftercare; Alleles; Amygdaloid structure; Animal Model; Behavior; Behavioral; Biological; Brain region; CRISPR/Cas technology; Candidate Disease Gene; Cell Nucleus; Cessation of life; Chronic; Complex; Data; Development; Etiology; Female; Future; Gene Targeting; Genes; Genetic; Genetic Variation; Genetic study; Genome; Genomic Segment; Genomics; Health; Human; Human Genome; Individual; Lead; Maps; Measures; Mediating; Modeling; Molecular; Mus; Neurobiology; Neuronal Plasticity; Neurons; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nucleus Accumbens; Pathway Analysis; Pathway interactions; Phenotype; Predisposition; Publishing; Quantitative Trait Loci; Relapse; Saline; Smoking; System; Time; Tissue-Specific Gene Expression; Tissues; Tobacco; Tobacco smoking behavior; Variant; Withdrawal; base; behavior change; candidate validation; differential expression; epidemiologic data; gene function; genetic architecture; genetic variant; genome editing; insight; mRNA sequencing; male; mouse genome; mouse model; nicotine abuse; nicotine cessation; nicotine exposure; nicotine use; novel; novel therapeutics; null mutation; resilience; response; smoking addiction; smoking cessation; therapy development; tool; trait; transcriptome; transcriptome sequencing; translational genetics

Project Summary Despite evidence of strong genetic contributions to the etiology of nicotine dependence (ND), we are far from identifying the specific genetic bases of individual susceptibility to ND. The primary objective of this proposal is to identify novel genetic factors that contribute to nicotine withdrawal, an important aspect of ND that contribute relapse, in mice. We observed pronounced nicotine withdrawal traits differences in C57BL/6NJ strain but not in the closely related C57BL/6J substrain. Because the parental substrains are nearly genetically identical, quantitative trait locus (QTL) mapping in an experimental F2 cross (Reduced Complexity Cross; RCC) will greatly facilitate the identification of novel genetic factors that underlie differences in withdrawal behaviors. In Aim 1, we will use the RCC to map genomic regions, or QTLs, that are causally associated with susceptibility versus resilience to multiple measures of nicotine withdrawal. In Aim 2, we will conduct transcriptome analysis via mRNA sequencing (RNA-seq) of four brain regions regions in control mice and chronic nicotine-treated mice from the parental male and female C57BL/6J and C57BL/6NJ substrains. The transcriptome in control mice will serve as a useful tool both in identifying candidate genes for future genome editing that are differentially expressed and underlie the behavioral QTLs as well as providing genomic insight into the neuronal context that influences susceptibility versus resilience to nicotine withdrawal. Genes that are differentially expressed as a consequence of nicotine will reveal changes in the transcriptome relevant to central neuronal plasticity and the behaviors/changes that support ND. In Aim 3, we will validate candidate quantitative trait genes and functional variants identified and ranked by Aims 1-2.

项目摘要 尽管有证据表明尼古丁依赖的病因学有很强的遗传贡献， (ND)，我们还远未确定个体易感性的特定遗传基础， ND.该提案的主要目的是鉴定新的遗传因子， 有助于尼古丁戒断，这是导致ND复发的一个重要方面， 小鼠我们观察到C57 BL/6 NJ在尼古丁戒断性状上的显著差异， 菌株，而不是在密切相关的C57 BL/6 J亚株。因为亲本亚株 几乎遗传相同，数量性状位点（QTL）定位在一个实验中， F2杂交（降低复杂性杂交; RCC）将极大地促进鉴定 新的遗传因素是导致戒断行为差异的基础。在目标1中，我们 使用RCC来绘制基因组区域，或QTL，这些区域与 对多种尼古丁戒断措施的敏感性与弹性。在目标2中， 将通过mRNA测序（RNA-seq）对四个脑组织进行转录组分析， 对照小鼠和长期尼古丁给药小鼠中来自亲本雄性的区域 以及雌性C57 BL/6 J和C57 BL/6 NJ亚株。对照小鼠的转录组将 作为一种有用的工具，既可以识别未来基因组编辑的候选基因， 是差异表达的，是行为QTL的基础， 对影响易感性与弹性的神经元背景的基因组洞察 尼古丁戒断基因差异表达的结果， 尼古丁将揭示与中枢神经元可塑性相关的转录组的变化 以及支持ND的行为/改变。在目标3中，我们将验证候选人 数量性状基因和功能变异体的鉴定和排序的目的1-2。